Osmotic drug delivery system

ABSTRACT

An oral osmotic pharmaceutical delivery system comprises a highly water-soluble drug exhibiting an erratic or an incomplete release profile when formulated in an elementary osmotic pump delivery system and at least one release enhancing agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.14/881,374, filed Oct. 13, 2015, which is a Divisional of U.S.application Ser. No. 14/265,630, filed Apr. 30, 2014, which is aContinuation of U.S. application Ser. No. 11/412,100, filed Apr. 27,2006, the entire contents of which are incorporated herein by reference.

The present invention is directed to the oral osmotic delivery oftherapeutic compounds that have high aqueous solubility but demonstratean erratic or incomplete, e.g., release from an elementary osmotic pump(EOP) delivery system, e.g., due to reduced solubility in the presenceof other components of a dosage form. The limited solubility in thepresence of other components of a dosage form often also results in anincomplete release. Medicinal agents that exhibit reduced solubility inthe presence of other components benefit from the release-enhancingagents (also know as release promoters) in the dosage form in order toachieve complete release. The present invention is directed to oralosmotic drug delivery systems for all therapeutic agents with inherenthigh solubility but limited release from an osmotic dosage form.

Extended release tablets that have an osmotically active drug coresurrounded by a semi-permeable membrane are known in the art. Theseosmotic dosage forms function by allowing water from gastric orintestinal fluid, to flow through the semi-permeable membrane anddissolve the active ingredient in the core so it can be released throughone or more passageways in the membrane. An elementary osmotic pump(EOP) delivery system requires that the drug is in solution in order tobe delivered in a controlled and predictable manner. The drug insolution is pumped out due to the osmotic gradient generated across thesemi-permeable membrane.

Solubility of the drug in aqueous media is usually used as a referenceto assess whether there is a need for a solubilizer in the coreformulation. Several drug delivery platforms were developed to overcomethe challenges of limited solubility of poorly soluble medicinal agents.If the drug is insoluble, an elementary osmotic pump system will notfunction properly. One approach for delivering pharmaceutical agentsthat are insoluble in aqueous solvents was developed by Kuczynski etal., (U.S. Pat. No. 5,545,413). In their approach, the interior of thetablet or capsule is characterized by two core layers, one containingthe pharmaceutical agent (again to be released through openings, orholes, in the wall of the tablet or capsule) and the other being a layerof material that swells when coming into contact with water. Thematerial that swells or expands to an equilibrium state when exposed towater or other biological fluids is referred to as an “osmopolymer”.This volume expansion is used to physically force the pharmaceuticalagent out through the openings, which have been formed in the wall,shell or coating during the manufacture. The pharmaceutical agent isprimarily released in the form of insoluble particles, which thereforehave limited bioavailability. This method has commonly been referred toas the “push/pull” approach. See, for example, U.S. Pat. Nos. 5,422,123;4,783,337; 4,765,989; 4,612,008; and 4,327,725. The patent literaturehas taught this approach for delivering adequate doses, at controlledrates and for extended times, of a broad variety of drugs.

Other osmotic delivery systems have also been described. See, forexample, U.S. Pat. Nos. 4,609,374; 4,036,228; 4,992,278; 4,160,020; and4,615,698. The osmopolymers used in these types of systems arecomponents whose function is to swell when they interact with water andaqueous fluids. This swelling effect is defined in these patents as aproperty of imbibing fluid so as to expand to a very high degree,usually exhibiting a 2- to 50-fold volume increase.

Rudnic et al., (U.S. Pat. Nos. 6,110,498; 6,284,276; 6,361,796, and6,514,532) used sodium lauryl sulfate and other solubilizers to enhancethe solubility of glipizide, a poorly soluble drug, to deliver it froman elementary type of osmotic system in a sustained manner. This systemof Rudnic is comprised of (a) a semi-permeable wall that maintains itsintegrity during pharmaceutical delivery, and which has at least onepassage there through; (b) a single, homogeneous composition within saidwall, which composition consists essentially of (i) a pharmaceuticallyactive agent, (ii) at least one non-swelling solubilizing agent whichenhances the solubility of the pharmaceutically active agent; (iii) atleast one non-swelling osmotic agent, and, optionally, (iv) anon-swelling wicking agent dispersed throughout the composition whichenhances the surface area contact of the pharmaceutical agent with theincoming aqueous fluid.

Thombre et al., (U.S. Pat. No. 5,697,922) used meglumine as asolubilizing agent for glipizide. This patent suggests coating megluminewith semi-permeable polymeric films to extend the release of thesolubilizer from the core. Thombre et at argued that non-encapsulatedsolubilizers would leave the core early, leaving the drug behind in anunsolubilized form. This loss of solubilizer results in an erraticrelease or no release at all. The problem with this approach is that itis very complex, because it involves coating of the solubilizingexcipient during the manufacture of the tablet. This process limits itspractical significance. Also, the amount of solubilizing excipient usedin this approach is exceedingly high. See also, U.S. Pat. No. 5,698,220,which discloses the use of 90% meglumine (aka, N-methylglucamine) in anosmotic dosage form for delivering glipizide.

This prior art does not address drugs that are highly water soluble whentested alone but manifest limited solubility and an erratic orincomplete release in the presence of other components of an osmoticdosage form.

The present invention overcomes the inadequacies of the prior art in thedelivery of medicinal agents that are highly soluble in water but havechallenges in release from osmotic dosage forms. While there are severalapproaches to deal with the delivery of poorly soluble drugs in osmoticdelivery systems, none of these approaches deal with the problem of anincomplete and erratic release of medicinal agents which are highlywater soluble but of limited solubility and release in the presence ofother components of a dosage form. Such drugs may be exemplified byprostacyclins that are valuable pharmacologically active compounds usedin the treatment of/for: pulmonary hypertension, pulmonary arterialhypertension (PAH), peripheral vascular disease (PVD), ischemic diseases(e.g. peripheral vascular disease, Raynaud's phenomenon, Scleroderma,myocardial ischemia, ischemic stroke; renal insufficiency), heartfailure (including congestive heart failure), conditions requiringanticoagulation (e.g. post MI, post cardiac surgery), thromboticmicroangiopathy, extracorporeal circulation, central retinal veinocclusion, atherosclerosis, inflammatory diseases (e.g. psoriasis),hypertension, cancer or other conditions of unregulated cell growth,cell/tissue preservation and other emerging therapeutic areas whereprostacyclin treatment appears to have a beneficial role.

Prostacyclins are characterized by a very short half-life ranging fromseveral minutes to several hours, which makes sustained oral delivery ofthis compounds problematic. A chemically stable analog of prostacyclin,treprostinil, has presented problems in sustained oral delivery with theprior art. Although treprostinil sodium (Remodulin®) is approved by theFood and Drug Administration (FDA) for subcutaneous and intravenousadministration, treprostinil as the free acid has an absolute oralbioavailability of less than 10%. Though oral preparations oftreprostinil have been disclosed (e.g. US Patent applications20050165111 and 20050282903, and U.S. Pat. No. 5,153,222, 5,028,628, and6,054,486), none of these publications addresses an issue of anerratic/incomplete release of treprostinil from oral controlled releasedosage forms. US patent publication 20050282901 to Phares discloses acomposition comprising a prostacyclin (treprosinil) and an additionalcardiovascular agent that enhances the oral bioavailability oftreprostinil. However, no teaching has been suggested for osmoticsustained release, high bioavailability preparations having treprostinilas the only active agent.

SUMMARY OF THE INVENTION

Accordingly, there is clinical interest in a safe and effective methodfor full and sustained delivery of treprostinil or its salts orderivatives via oral administration. This invention pertains to anosmotic drug delivery system that incorporates release-promotingagent(s) (release enhancers) to achieve complete and predictable releaseof such medicinal agents. It additionally pertains to the methods fororal delivery of prostacyclins, treprostinil in particular, in sustainedrelease solid dosage forms.

The present invention provides for complete and predictable release ofhighly water-soluble medicinal agents (thus not ignoring a solubilityenhancer(s)) with water solubility of at least 30 mg/ml or higher, whoserelease from an osmotic controlled/sustained release dosage form, i.e.,a standard osmotic delivery system, is erratic and/or incomplete. Forthe purposes of this invention, an erratic release is defined as aninconsistent release among tablets of similar composition (mean (n=6)percent released differing by more than 25%), and an incomplete releaseis defined as less than complete release (80% or less) in 10-12 Hrs fora drug given twice a day; 80% or less in 16-24 Hrs for a drug that isgiven once a day.

These erratic and/or incomplete releases refer to in vitro release,measured conventionally, e.g., by USP dissolution method described inthe Figures.

By a “standard osmotic delivery system” herein is meant an elementaryosmotic pump (EOP) system. An EOP is very well known to those skilled inthe art. This system can be used to test for drugs which are “erratic”or give an incomplete release profile, as defined. See, e.g., FelixTheeuwes, Elementary Osmotic Pump, Journal of Pharmaceutical Sciences,Vol. 64, No. 12, Pp 1987-1991, December 1975.

The release enhancing agents (also called release promoters) used inthis invention promote the release of the medicinal agents whiledelivering the drug in a controlled and predetermined rate. The presentinvention also provides for controlled and sustained release of a classof medicinal agents, such as the prostacyclins, which exhibit a veryshort half-life ranging from several minutes up to three hours,exemplified here by treprostinil or its salts or derivatives.

The invention pertains to the oral delivery of such agents in acontrolled and predictable manner to meet specific therapeutic goals.Preferably, the invention relates to drugs and systems wherein in vivorelease profiles (C_(MAX) and/or AUC and/or T_(MAX)) can be accuratelypredicted from standard in vitro dissolution profiles, e.g, withsufficient reliability to routinely achieve desired in vivo profiles.

Other objects, features, and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the presentinvention; are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from the detaileddescription.

BRIEF DESCRIPTION OF DRAWINGS

Various features and attendant advantages of the present invention willbe more fully appreciated as the same becomes better understood whenconsidered in conjunction with the accompanying drawings, in which likereference characters designate the same or similar parts throughout theseveral views, and wherein:

FIG. 1 depicts the dissolution profiles of Treprostinil Diethanolamineosmotic tablets with and without release enhancing agents using a USPApparatus II at 50 RPM, Dissolution medium: of phosphate bugger (pH6.8).

FIG. 2 shows the effect of dissolution of Treprositinil DiethanolamineOsmotic Tablets under various dissolution conditions (dissolution media,paddle speed) using USP Apparatus II.

FIG. 3 shows the effect of coating levels (by weight) on the release oftreprostinil from Treprostinil Diethanolamine osmotic tablets.

FIG. 4 shows dissolution profiles of Treprostinil Diethanolamine osmotictablets coated to 3% weight gain and drilled to various hole sizes.

FIG. 5 shows the dissolution profiles of Treprostinil Diethanolamineosmotic tablets containing varying amounts of the active drug (1 mg, 5mg, and 10 mg).

FIG. 6 shows the pharmacokinetic profiles in humans of TreprostinilDiethanolamine osmotic tablet and a reference tablet formulation versusan oral solution.

FIG. 7 shows the pharmacokinetic profiles of Treprostinil Diethanolamine1 mg osmotic tablet when given with and without food.

The present invention provides an alternative to solving the problem ofthe controlled release, osmotic delivery of pharmaceutical agents thathave high aqueous solubility (at least 30 mg/ml), and preferably, do notneed or benefit from solubility enhancers as in the prior art, butrather unpredictable solubility in the presence of other coreexcipients. Unpredictable and erratic solubility in the core formulationresults in the unpredictable and rather low extent of drug release. Sucherratic solubility in the core also exacerbates the effects of externalenvironmental variables such as pH, agitation, and ionic strength on therate and extent of drug release from the dosage form. These solubilityand delivery difficulties are overcome by incorporation into an osmoticdelivery system of the present invention of release enhancing agentsselected to enhance the solubility of the drug in the core irrespectiveof the core environment and to enable the complete release of such drugsfrom an osmotic system. Thus, an osmotic delivery system of the presentinvention comprises: a) at least one medicinal agent with high aqueoussolubility that exhibits limited and/or erratic and unpredictablerelease when formulated into an osmotic dosage from; (b) at least onerelease enhancing agent; (c) at least one osmotic agent; (d) optionally,a binder to aid tableting; (e) optionally, at least one lubricant to aidthe tableting process; (f) typically at least one coating polymer; (g)optionally, at least one plasticizer.

For the purpose of this application, the following definitions of termsare given:

The terms “complexing agents” and “micelle forming agents” are usedherein as described in Chapters 14 and 20, respectively, of the 20^(th)edition of Remington's The Science and Practice of Pharmacy (20^(th)ed., Lippincott, Williams and Williams, 2000).

A wicking agent is defined as any material with the ability to drawwater into the network of a delivery dosage form. By so doing, a wickingagent provides enhanced flow channels for the pharmaceutical agent whichhas been made predominantly into its solubilized form.

Suitable release enhancing agents include wicking agents, such as highHLB surfactants (for example Tween 20, Tween 60 or Tween 80; ethyleneoxide propylene oxide block copolymers (aka Pluronics®),), ionicsurfactants such as sodium lauryl sulfate, sodium docusate, non-swellinghydrophilic polymers such as cellulose ethers, and polyethylene glycols(PEGs); complexing agents such as: polyvinyl pyrrolidone, cyclodextrinsand non-ionic surface active agents; and micelle forming agents, whichmay be surface active agents such as Tweens (Poly(ethylene Oxide)modified sorbitan monoesters), Spans (fatty acid sorbitan esters),sodium lauryl sulfate, and sodium docusate.

The release enhancing agents are incorporated in the core tablet formulaand constitute from 0.5% to 90% by weight of the formula, preferablyfrom 1% to 50%. Most preferably, release-enhancing agents constitutefrom 1% to 20% by weight of the formulation. They can be incorporatedduring granulation or post-granulation. The release enhancing agent(s)can be added in the form of solid powder or can be dissolved in thegranulating liquid and sprayed during granulation. In order to achieveintimate mixing with the drug(s) the release enhancing agent can bemixed with the drug alone before the other excipients are incorporated.Alternatively, the release enhancing agent(s) and the drug can bedissolved in the granulating liquid and sprayed during granulation. Inyet another way, the release enhancing agent(s) and the drug can bedissolved in a solvent, and when the solution is dried, the solid massthus obtained can be milled and then mixed with the rest of theexcipients for further processing.

Osmotic agents are well known to those skilled in the art. Osmoticagents suitable for the present invention are simple sugars such assucrose, xylitol, glucose, lactose; salts such as sodium chloride,potassium chloride; low molecular weight hydrophilic polymers such ascellulose ethers, maltodextrins, and cyclodextrins. Osmotic agents canbe incorporated in the formulation of this invention in the amount offrom 1% by weight to 90% by weight, preferably from 5% to 80% and mostpreferably from 10% to 80% by weight. Osmotic agents are typicallyincorporated in the formula during granulation.

The granules can also be blended with other excipients as needed to aidthe manufacturing of the desired dosage form: tablets, capsules orpellets. Tablets are compressed on a standard rotary tablet press.

The core tablet is typically coated with a semi-permeable membranecontaining at least one plasticizer. The coating polymer is dissolvedwith at least one plasticizer in an appropriate solvent or a mixture ofsolvents and sprayed on the tablets for coating. The coating polymersinclude, but are not limited, to cellulose acetate. The coating membranepreferably also contains at least one plasticizer to improve flexibilityand durability of the coat. Such plasticizers include, but are notlimited to, triethyl citrate (TEC), propylene glycol (PG), or mixturesthereof in ratios of TEC to PG ranging from 25:75 to 75:25; Tween 80,polyethylene glycols (PEGs); other polyoxyethylene sorbitan esters,triacetin, diethyl phthalate, mineral oil, tributyl sebacate, andglycerol. The coating level can vary from 1% to 25%, preferably from 2%to 20%, and most preferably from 3% to 10% by weight.

The semi-permeable wall also includes at least one opening to providefor the osmotic delivery of the drug(s). In general the at least oneopening has a diameter of from 50 μm to 1000 μm, preferably from 100 μmto 800 μm. The opening is formed by drilling using a laser or any otherappropriate hole drilling system. The opening can be of any shape. Thevarious shapes contemplated for this invention include, but are notlimited to round, cross-shaped, rectangular, diamond, star, and squareshapes. As the dosage unit (osmotic tablet) imbibes water, therelease-enhancing agents go into solution providing an environment forthe drug to dissolve. The osmotic agent(s) in the core tablet drawswater into the core tablet creating an osmotic gradient across thesemi-permeable membrane. The osmotic gradient pushes the drug in thesolution out through the laser-drilled hole.

This invention is not limited to a particular dosage form such astablets. The dosage form containing the appropriate release-enhancingagents can be prepared, e.g., in the form of capsules or pellets. Oncethe capsule is filled with the appropriate combination of drugs,release-enhancing agents and excipients, it is coated with asemi-permeable membrane. At least one opening is drilled through thesemi-permeable membrane to allow drug release.

The oral osmotic delivery system of the present invention provides for acomplete and predictable release of drugs with high water solubility butwith an incomplete or erratic release from a standard osmoticformulation. This complete and predictable release is achieved byincorporation of at least one release-enhancing agent into theformulation. The release of such drugs from the formulation of theinvention is unaffected by the core environmental variables such as pHand ionic strength. Such release is also independent on the extent ofagitation. Therefore, the dosage form of the invention is robust andprovides predictable release of the medicinal agent. The dosage formalso provides in vivo release profiles that can be predicted based on invitro release profiles. The dosage form in accordance with thisinvention additionally provides for a controlled release of a medicinalagent that allows for a twice to once daily administration to achievetherapeutic value. Such administration improves patient compliance. Thecontrolled delivery of the medicinal agent will result in an essentiallyflat pharmacokinetic profile that reduces side effects associated withspikes in blood concentration of the medicinal agent.

The present invention is exemplified by treprostinil, a drug withparticularly poor oral delivery and a short half-life, which haspresented problems with the prior art technology. Treprostinil is achemically stable analog of prostacyclin and is approved by the Food andDrug Administration (FDA) for subcutaneous and intravenousadministration using a specialized pump to deliver the drug over anextended period of time. This pump allows for the delivery of the drugto the patient at a controlled rate. The drawbacks to this mode ofadministration are that it is complex, expensive and results in areaction at the site of the injection. The present invention providesfor an oral delivery of this drug at a controlled rate that results in aflat pharmacokinetic profile. The advantages of a controlled sustainedrelease oral administration over injection are valuable to those skilledin the art. Particularly, the present invention provides an orallyadministered sustained release formulation of Treprostinil effective toproduce plasma concentrations varying between a Cmin of 0.1 to 0.2 ng/mlto a maximum plasma concentration of treprostinil of about 0.5 ng/ml toabout 2 ng/ml for a time of about 2 hours to 8 hours. The formulationmay be designed to provide desired steady-state blood levels of the drugin a twice-a-day regimen. Still further, the formulation may be adjustedto once-daily dosing of treprostinil in an extended release preparationthat also provides a desired therapeutically effective plasma drugconcentration profile.

The present invention also provides a method of using prostacyclins, andespecially treprostinil, therapeutically of/for: pulmonary hypertension,pulmonary arterial hypertension (PAH), ischemic diseases, heart failure,conditions requiring anticoagulation, thrombotic microangiopathy,extracorporeal circulation, central retinal vein occlusion,atherosclerosis, peripheral vascular disease, inflammatory diseases,hypertension, cancer or other conditions of unregulated cell growth,cell/tissue preservation and other emerging therapeutic areas whereprostacyclin treatment appears to have a beneficial role. A preferredembodiment of the invention is a method of treating pulmonary arterialhypertension and/or peripheral vascular disease in a subject comprisingorally administering a pharmaceutically effective amount of aprostacyclin analogue in a sustained-release osmotic dosage formulation.

In addition to prostacyclins, other therapeutic agents will benefit fromthis invention. They may be represented by such highly water solublepharmaceutical agents as antidepressants, for example citalopram HCl,fluoxetine HCl, and protriptyline; antipsychotic agents, such asmolindone HCl and chlorpromazine HCl; anxiolytic agents such astrifluperazine HCl and clorazepate dipotassium; antibiotics such asbleomycin sulfate and clindamycin HCl; antihypertensive agents such asatenolol, lisinopril, metoprolol succinate, bisoprolol fumarate,hydrochlorothiazide, quinapril HCl, propranolol HCl, perindoprilerbumine, enalapril maleate, and captopril, among others; antineoplasticagents such as terazosin HCl and tamoxifen citrate; drugs used to treatParkinson's disease, for example biperidine HCl; antiepileptic drugs,such as gabapentin and tiagabine HCl, anticholinergic drugs, such asglycopyrrolate and, trospium chloride; antiallergics such aspromethazine HCl; antiangina drugs such as isosorbide dinitrate andnadolol; drugs for treatment of an orthostatic hypotension such asmidodrine HCl; attention deficit hyperactivity disorder (ADHD) drugssuch as amphetamines; pain management medications such as hydromorphoneHCl, codeine phosphate and meperidine HCl, and any other highly watersoluble drugs not mentioned above whose complete release from a standardosmotic dosage form is not achieved. Unless otherwise specified, “a” or“an” means “one or more”. As will also be understood by one skilled inthe art, all language such as “up to,” “at least,” “greater than,” “lessthan,” “more than” and the like include the number recited and refers toranges which can be subsequently broken down into subranges as discussedabove. In the same manner, all ratios disclosed herein also include allsubratios falling within the broader ratio. Furthermore, one skilled inthe art will also readily recognize that where members are groupedtogether in a common manner, such as in a Markush group, the presentinvention encompasses not only the entire group listed as a whole, buteach member of the group individually and all possible subgroups of themain group. Other objects, features, and advantages of the presentinvention will become apparent from the following examples. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the presentinvention, are given by way of illustration only, since various changesand modifications within the spirit and scope of the invention willbecome apparent to those skilled in the art from the detaileddescription.

EXAMPLES

In order that this invention may be better understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any manner. Numerous other variations of the presentinvention will be appreciated by those skilled in the art, in view ofthe disclosure herein. The exact compositions, methods of preparationand embodiments shown are not limiting of the invention, and any obviousmodifications will be apparent to one skilled in the art.

Example 1 Granulation of Treprostinil Osmotic Formulation ContainingSodium Lauryl Sulfate and Meglumine as Release Enhancing Agents

Table 1 provides composition of the Treprostinil osmotic tablet coresmade with and without release enhancing agent:

TABLE 1 Composition of Treprostinil osmotic granulation With releaseIngredients No Release enhancers Treprostinil diethanolamine 0.635%  0.65% Xylitol 41.0% 41.00% Maltrin M150 (wet) 1.60%  1.40% Maltrin M150(dry) 53.0% 48.20% Sodium Phosphate   3% — Sodium Lauryl Sulfate — 5.00% Meglumine —  3.00%

All ingredients were screened through an 18-mesh sieve prior togranulation. Granules were manufactured by top spray granulation inGlatt's fluid bed granulator (GPCG-1 or GPCG-15 (Glatt® Air TechniquesInc., Ramsey, N.J.). Two spray solutions were prepared. One solutioncontained Maltrin M150 (used as a binder), and the drug, treprostinil.The second solution contained Maltrin M150 only. Prescreened ingredientswere charged in to the fluid bed granulator. Spray solution 1 wassprayed first followed by spray solution 2. The granulation processparameters are given in Table 2. Once all the spray solutions have beensprayed, the granules were dried in the fluid bed while monitoring themoisture level. A moisture level of less than 3% was consideredacceptable. Dried granules were screened through an 18-mesh sieve.

TABLE 2 Granulation processing parameters 2 Kg scale 10 Kg scale Fluidbed Granulator GPCG-1 GPCG-15 Typical batch size (kg) 2 10 Inlet airtemperature (° C.) 58-63 58-63 Exhaust air temperature (° C.) 28-3128-31 Product temperature (° C.) 31-33 31-33 Air volume (m/s for GPCG1 4400-500 and CFM for GPCG-15) Spray rate (gm/min) 8-9 120-150

Example 2 Tableting of Granules from Example 1

Screened granules from Example 1 were blended with magnesium stearate ina V-blender for 3-5 minutes. The blend was tableted on a Rotary tabletpress using a 5/16″ round standard concave tooling (punches and dies).Tablet weight, hardness, and thickness were monitored throughout thecompression run. Tablets were also analyzed for an assay and contentuniformity.

Table 3 provides the composition of treprostinil core tablets:

TABLE 3 Composition of Treprostinil osmotic tablets No Release ReleaseIngredients enhancer enhancer(s) Treprostinil diethanolamine 0.635% 0.65% Xylitol  41.0% 41.00% Maltrin M150 (wet)  1.60%  1.40% MaltrinM150 (dry)  53.0% 48.20% Na Phosphate   3% — Sodium Lauryl Sulfate — 5.00% Magnesium stearate  0.75%  0.75%

Example 3 Coating of Tablets from Example 2

Core tablets from Example 1 were coated with a coating system containingcellulose acetate as a polymer and Poly(ethylene glycol) 3350 (PEG3350)as a plasticizer. Coating was performed in LDCS-III pan coater (VectorCorporation, Marion, Iowa). The coating solution was sprayed on thetablets in a rotating perforated pan until the desired coating level wasachieved.

Example 4 Drilling Coated Tablets from Example 3 Using Laser TabletDrilling System

A hole was drilled on the coating of the tablets from Example 3 usingLumonics laser tablet drilling system (Resonetics Inc, Nashua, N.H.).The laser power and beam diameter is adjusted to achieve desired holesize. Drilled tablets were evaluated for assay, content uniformity anddissolution.

FIG. 1 shows the dissolution profiles for tablets from Example 5.Dissolution was conducted using USP Apparatus II at a paddle speed of 50RPM. The dissolution medium was 50 mM phosphate buffer at pH 6.8. Therelease of treprostinil from the osmotic tablets containing releaseenhancer(s) can be described by a T₁₀ (time to release 10%) of 0.25 Hr-1Hr; T₅₀ (time to release 50%) of 2 Hrs-5 Hrs, and T₈₀ (time to release80% of 6 Hrs-12 Hrs.

Example 5 Granulation and Tableting of Formulations Containing SodiumLauryl Sulfate (SLS) as a Release Enhancing Agent

TABLE 4 Composition of SLI539 CTM granules, uncoated and coated tabletsFormulation Granules Uncoated Tablets Coated Tablets Treprostinildiethanolamine  0.65%  0.65%  0.63% Xylitol CM90 43.32% 43.00% 41.71%Maltrin M150 (wet)  1.41%  1.40%  1.36% Maltrin M150 (dry) 49.57% 49.20%47.72% Sodium Lauryl Sulfate  5.04%  5.00%  4.85% Magnesium Stearate N/A 0.75%  0.73% Cellulose Acetate N/A N/A  2.40% Triethyl Citrate N/A N/A 0.60% Total   100%   100%   100%

Table 4 provides the granules and tablet composition. Granuleswere-manufactured by top spray granulation in a fluid bed granulator(GPCG-1 for 2 kg scale and GPCG-15 for the 10 kg scale batches). Twospray solutions were prepared. One solution contained Maltrin M150 (usedas a binder), and Treprostinil diethanolamine. The second solutioncontained Maltrin M150 only. All ingredients were screened through an18-mesh sieve. Sieved ingredients were charged in to the fluid bedgranulator. Spray solution 1 was sprayed first followed by spraysolution 2. Granulation process parameters are provided in Table 2. Onceall the spray solutions have been sprayed, the granules were dried inthe fluid bed granulator while monitoring the moisture level. A moisturelevel of less than 3% was considered acceptable. Dried granules werescreened through an 18-mesh sieve. Dry granules were blended withmagnesium stearate in a PK V-blender fitted with an appropriate sizeshell. The blend time was 3-5 minutes. The blend was then compressed ona rotary tablet press using a standard 5/16″ concave tooling. Tabletweight, hardness and thickness were monitored throughout the compressionrun.

Example 6 Coating and Drilling of Tablets from Example 5

TABLE 5 Coating solution composition (% by weight) Ingredients TEC/CACellulose acetate 5 Triethyl citrate (TEC) 1.25 Acetone 93.75 Total 100

Table 6 provides the tablet coating process parameters.

TABLE 6 Pan coating process parameters Coating System TEC/CA Pan CoaterO'Hara Pan Coater Typical batch size (kg) 3.5-4.0 Inlet air temperature(° C.) 38 Exhaust air temperature (° C.) 26-31 Air Flow (CFM) 110 Sprayair (PSI) 23 Pattern Air (PSI) 23 Pan rotation (RPM) 12 Spray rate(gm/min) 30-50 Curing Inlet air temperature (° C.) 38 Exhaust airtemperature (° C.) 26-31 Air Flow (CFM) 110 Spray air (PSI) N/A PatternAir (PSI) N/A Pan rotation (RPM) 10 Spray rate (gm/min) N/A Cool downInlet air temperature (° C.) Heat Off Exhaust air temperature (° C.) N/AAir Flow (CFM) 110 Spray air (PSI) N/A Pattern Air (PSI) N/A Panrotation (RPM) 10 Spray rate (gm/min) N/A

Tablets were charged in to the pan coater and jogged to warm-up. Coatingsolution was sprayed while monitoring the exhaust temperature. Tabletswere coated to various coating levels by weight. Table 6 provides thecoating process parameters used. Coated tablets were drilled as inExample 2, and the drilled tablets were tested for dissolution. Thedissolution profiles of tablets made in this example are given in FIGS.2-5.

The dissolution profiles obtained can be described by T₁₀ (time torelease 10%) of 0.25 Hr-1 Hr; T₅₀ (time to release 50%) of 2 Hrs-5 Hrs,and T₈₀ (time to release 80%) of 6 Hrs-12 Hrs. FIG. 2 shows the effectof dissolution conditions (paddle speed, ionic strength of thedissolution medium, pH of the dissolution medium) on the release oftreprostinil from osmotic treprostinil tablets. FIG. 3 shows the effectof coating levels (by weight) on the release of treprostinil fromosmotic treprostinil tablets. FIG. 4 shows the effect of an openingdiameter on the release of treprostinil. Shown in FIG. 5 are thedissolution profiles of osmotic treprostinil tablets containing varyingamounts of the active drug.

Example 7 Human Pharmacokinetic Study of Treprostinil Osmotic Tabletsfrom Example 6

The objective was to compare the safety and PK profile of the 12 HrTreprostinil Osmotic tablet formulation (lot #B05005) with an 8 HrSustained Release (SR) tablet formulation in healthy volunteers.Subjects (n=10) received a single dose (1 mg) of the osmotic formulationin either fasted state or fed state (standard FDA meal). Subjects thenhad a washout period of 7 days and then returned to the clinic toreceive the crossover treatment. On the dosing days, PK samples werecollected out to 24 Hr post dose and safety was assessed until dischargefrom the clinic. PK samples were analyzed by a validated LC/MS/MS assay.The pharmacokinetic profiles are given in FIG. 7. Results show that theOsmotic tablet formulation provides an extended systemic exposurecompared to the 8 Hr SR (sustained release) tablet formulation.

Example 8 Effect of Food on the Pharmacokinetics of Treprostinil from anOsmotic Treprostinil Tablet

The objective was to compare the safety and PK profile of the 12 HrTreprostinil Osmotic tablet formulation (lot #B05005) in the fed andfasted state in healthy volunteers. Subjects (n=10) received a singledose (1 mg) of the osmotic formulation in either the fasted state or fedstate (standard FDA meal). Subjects then had a washout period of 7 daysand then returned to the clinic to receive the crossover treatment. Ondosing days, PK samples were collected out to 24 Hr post dose and safetywas assessed until discharge from the clinic. PK samples were analyzedby a validated LC/MS/MS assay. The pharmacokinetic profiles are given inFIG. 7. Results showed there was a difference in the PK profiles betweenthe fed and fasted states with the fed state exhibiting longer durationof treprostinil systemic exposure. Safety parameters were similarbetween the fed and fasted states with very good overall tolerability.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publicationscited herein are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1. A method of treating pulmonary hypertension in a human subjectcomprising administering to the human subject a solid oral dosage formcomprising: (a) an osmotically-active drug core comprising (i)treprostinil in the form of treprostinil diethanolamine and (ii) atleast one release-enhancing agent; and (b) a semi-permeable membranesurrounding the osmotically-active drug core, wherein the semi-permeablemembrane comprises at least one opening to permit osmotic release of thetreprostinil from the osmotically-active drug core, wherein theadministration provides a therapeutically effective plasma concentrationof treprostinil in the human subject.
 2. The method of claim 1, whereinthe administering is performed twice a day.
 3. The method of claim 2,wherein the administering results in steady-state blood levels of thetreprostinil.
 4. The method of claim 1, wherein the therapeuticallyeffective plasma concentration of treprostinil in the human subject hasa T_(max) of 2 hours to 8 hours.
 5. The method of claim 1, wherein thetherapeutically effective plasma concentration of treprostinil in thehuman subject has a C_(max) of 0.5 ng/ml to 2 ng/ml.
 6. The method ofclaim 1, wherein the therapeutically effective plasma concentration oftreprostinil in the human subject has a C_(min) of 0.1 ng/ml to 0.2ng/ml.
 7. The method of claim 1, wherein the solid oral dosage formcomprises 1 mg of treprostinil.
 8. The method of claim 1, wherein the atleast one opening has a diameter of from 100 μm to 800 μm.
 9. The methodof claim 1, wherein the semi-permeable membrane comprises multipleopening.
 10. The method of claim 1, wherein the at least one releaseenhancing agent is selected from a group consisting of wicking agents,complexing agents, and micelle-forming agents.
 11. The method of claim10, wherein the wicking agents are selected from the group consisting ofhigh HLB surfactants, ionic surfactants, and non-swelling hydrophilicpolymers.
 12. The method of claim 10, wherein the complexing agents areselected from the group consisting of polyvinyl pyrrolidone,cyclodextrins, and non-ionic surface active agents.
 13. The method ofclaim 10, wherein the micelle-forming agents are selected from the groupconsisting of poly(ethylene oxide) modified sorbitan monoesters, fattyacid sorbitan esters, sodium lauryl sulfate, and sodium docusate. 14.The method of claim 1, wherein the release-enhancing agent is sodiumlauryl sulfate.
 15. The method of claim 1, wherein the at least onerelease-enhancing agent constitute from 1% to 20% by weight of theformulation.
 16. The method of claim 1, wherein the osmotically-activedrug core further comprises at least one osmotic agent.
 17. The methodof claim 16, wherein the osmotically-active drug core comprises xylitoland maltodextrin.
 18. A method of treating pulmonary hypertension in ahuman subject comprising administering to the human subject a solid oraldosage form comprising: (c) an osmotically-active drug core comprising(i) treprostinil diethanolamine and (ii) sodium lauryl sulfate; and (d)a semi-permeable membrane surrounding the osmotically-active drug core,wherein the semi-permeable membrane comprises at least one openinghaving a diameter from 100 μm to 800 μm to permit osmotic release of thetreprostinil from the osmotically-active drug core, wherein theadministration provides a therapeutically effective plasma concentrationof treprostinil in the human subject, wherein the therapeuticallyeffective plasma concentration of treprostinil in the human subject hasa T_(max) of 2 hours to 8 hours, wherein the therapeutically effectiveplasma concentration of treprostinil in the human subject has a C_(max)of 0.5 ng/ml to 2 ng/ml, and wherein the therapeutically effectiveplasma concentration of treprostinil in the human subject has a C_(min)of 0.1 ng/ml to 0.2 ng/ml. wherein the therapeutically effective plasmaconcentration of treprostinil in the human subject has a C_(max) of 0.5ng/ml to 2 ng/ml, and wherein the therapeutically effective plasmaconcentration of treprostinil in the human subject has a C_(min) of 0.1ng/ml to 0.2 ng/ml.